Our prior work at the NCI led to the FDA approval of a PET-imaging agent, Ga-68 DOTATATE, a high affinity ligand that binds somatostatin receptor (SSTR). These cancers are very rare and are unique in that they have characteristic surface receptor repertoire, the somatostatin receptors 1-5 (most prevalent SSTR2), that not only help identify them as neuroendocrine tumors, but also represent key pro-growth and pro-survival pathways. In aggressive or metastatic neuroendocrine tumors, that are not amenable to surgical resection, a novel radiolabeled SSTR2 analogs for the therapy of metastatic lesions (Lu177-DOTATATE) has been used. Unfortunately, with dedifferentiation, the tumors lose SSTR2 expression, and renders them invisible or not amenable for targeted therapy. SSTR2 expression is controlled by epigenetic mechanisms. Studies have shown that epigenetic drugs manage to modulate or even upregulate this receptor. Our studies will identify several candidate genes and mechanisms that are dysregulated in neuroendocrine cancers and have an important role in tumor cell biology. We will use molecular inhibitors or stimulators to test whether targeting these epigenetic mechanisms will affect tumor growth, metastasis and upregulation of targets, and ultimately the response to therapy. We will also evaluate molecular targets for therapy in a xenograft and metastatic mouse model for pancreatic and gastro-intestinal neuroendocrine cancers.